Sporadic Alzheimer's disease (AD) is a late-onset dementia of unknown etiology, characterized by the presence of amyloid b (A?) containing senile plaques, neurofibrillary tangles, and cognitive decline. Importantly, the inheritance of Apolipoprotein (APOE) allele is the only established risk factor for sporadic late onset AD. However, the mechanism underlying this association remains elusive. ATP binding cassette transporter A1 (ABCA1) regulates cholesterol efflux from cells to cholesterol acceptors, primarily poorly lipidated apolipoprotein A-I (APOA-I) and APOE thus generating nascent high density lipoprotein (HDL). Disruption of Abca1 in APP expressing mice increased plaque levels in brain parenchyma and cerebral amyloid angiopathy. Remarkably this was accompanied by abnormal HDL-like particle structure in the CSF and decreased levels of APOA-I and APOE. Thus, processes that regulate APOE expression and lipidation could affect its ability to influence brain homeostasis. In support of this hypothesis the lower level of APOE in carriers is associated with increased pathology and AD risk. Furthermore, stimulation of APOE expression and lipidation with LXR and RXR agonists is associated with reduced pathology and improved cognition in AD mouse models. The central hypothesis is that Abca1 affects formation/deposition and clearance, through lipidation of ApoE and formation of HDL, therefore therapeutic approaches which affect the levels of Abca1 and ApoE can be used to treat the pathology. To prove the hypothesis we use viral vectors to overexpress apolipoproteins and multiphoton microscopy to assess in vivo the effects on A pathology and neuronal abnormalities in APP transgenic mice. Furthermore, we will characterize the effects of a clinically significant mutation of ABCA1 on APP mouse model phenotype. Lastly, we will examine how changes in peripheral and central expression of Abca1 affect lipid profiles and amyloid levels. The completion of this application will have a significant impact on our understanding of how different APOE alleles and a clinical relevant mutation of ABCA1 effects amyloid pathology. The design will allow for much more insight into a possible mechanism by which APOE affects AD progression. Furthermore, the application will further our understanding of the importance of central and peripheral ABCA1 in brain lipid profiles and amyloid levels, allowing for improved treatment targets. TRAINING IN THE RESPONSIBLE CONDUCT OF RESEARCH: Acceptable. The candidate has successfully completed training in the past and proposes additional focused training to supplement this background. The procedures for protection from research risks are satisfactory. Women and minorities are appropriately included in the research.